Over half a million interventional intravascular procedures are performed each year. While such invasive procedures continue to improve over time, as many as 30-50% of the procedures performed each year fail as a result of restenosis. The reduction of restenosis is, therefore, often cited as the most critical factor in increasing the success realized in the treatment of cardiovascular disease through the use of interventional intravascular procedures, such as angioplasty, atherectomy, and procedures utilizing stents and laser technology.
In balloon angioplasty, for example, a small incision is made to an artery in the patient's leg or arm and a long hollow tube, called a guide catheter, is inserted into the artery. A thick guide wire and deflated balloon catheter are then inserted into the guide catheter and are carefully advanced through the patient's blood vessels using x-ray visualization. The deflated balloon is advanced until it reaches the site of the luminal narrowing, at which point the physician inflates the balloon one or more times to a pressure of about 4-6 atm for about 60 sec. When inflated, the balloon cracks and fractures the plaque and stretches the muscle fiber in the artery wall beyond its ability to recoil completely. Although no plaque is removed in this procedure, the fracturing of the plaque and the stretching of the arterial wall increase the vessel lumen, thereby allowing for increased blood flow through the lumen.
The restenosis that accompanies such procedures is characterized by platelet aggregation and adhesion, smooth muscle cell proliferation, narrowing of the vessel lumen, restricted vasodilation, and an increase in blood pressure. Smooth muscle cells in the intimal layer of the artery have been reported to enter the growth cycle within about 2-3 days of these procedures and to proliferate for several days thereafter (intimal hyperplasia), the vast majority of smooth muscle cell proliferation reportedly being completed within 7 days (Stemerman, Am. J. Pathol. 73: 7-18 (1973)). Attempts have been made to provide nitric oxide as a means of treating platelet aggregation and the like.
Nitric oxide in its pure form, however, is a highly reactive gas having limited solubility in aqueous media (WHO Task Group on Environmental Health Criteria for Oxides of Nitrogen, Oxides of Nitrogen, Environmental Health Criteria 4 (World Health Organization: Geneva, 1977)). Nitric oxide, therefore, is difficult to introduce reliably into most biological systems without premature decomposition.
A number of compounds have been developed which are capable of delivering nitric oxide, including compounds which release nitric oxide upon being metabolized and compounds which release nitric oxide spontaneously in aqueous solution.
Those compounds which release nitric oxide upon being metabolized include the widely used nitrovasodilators glyceryl trinitrate and sodium nitroprusside (Ignarro et al., J. Pharmacol. Exp. Ther., 218, 739-749 (1981); Ignarro, Annu. Rev. Pharmacol. Toxicol., 30, 535-560 (1990); Kruszyna et al., Toxicol. Appl. Pharmacol., 91, 429-438 (1987); Wilcox et al., Chem. Res. Toxicol., 3, 71-76 (1990)), which are relatively stable but release nitric oxide on activation. While this feature may be an advantage in some applications, it also can be a significant liability. For example, tolerance to glyceryl trinitrate can develop via the exhaustion of the relevant enzyme/cofactor system (Ignarro et al., Annu. Rev. Pharmacol. Toxicol., 25, 171-191 (1985); Kuhn et al., J. Cardiovasc. Pharmacol., 14 (Suppl. 11), S47-S54 (1989)). Also, prolonged administration of nitroprusside results in the metabolic production of cyanide, which leads to toxicity (Smith et al., "A Potpourri of Biologically Reactive Intermediates" in Biological Reactive Intermediates IV. Molecular and Cellular Effects and Their Impact on Human Health (Witmer et al., eds.), Advances in Experimental Medicine and Biology Volume 283 (Plenum Press: New York, 1991), pp. 365-369). S-Nitroso-N-acetylpenicillamine has been reported to release nitric oxide in solution and to be effective at inhibiting DNA synthesis (Garg et al., Biochem. and Biophys. Res. Comm., 171, 474-479 (1990)).
Numerous nitric oxide-nucleophile complexes have been described, e.g., Drago, ACS Adv. Chem. Ser., 36, 143-149 (1962). See also Longhi and Drago, Inorg. Chem., 2, 85 (1963). Some of these complexes are known to evolve nitric oxide on heating or hydrolysis, e.g., Maragos et al., J. Med. Chem., 34, 3242-3247 (1991).
A very important class of such agents is the just-named nitric oxide-nucleophile complexes (NONOates). Recently, a method for treating cardiovascular disorders in a mammal with certain nitric oxide-nucleophile complexes was disclosed, e.g. in U.S. Pat. No. 4,954,526. These compounds contain the anionic N.sub.2 O.sub.2.sup.- group or derivatives thereof. See also, Maragos et al., supra. Many of these compounds have proven especially promising pharmacologically because, unlike nitrovasodilators such as nitroprusside and nitroglycerin, they release nitric oxide without first having to be activated. The only other series of drugs currently known to be capable of releasing nitric oxide purely spontaneously is the S-nitrosothiol series, compounds of structure R--S--NO (Stamler et al., Proc. Natl. Acad. Sci. U.S.A., 89, 444-448 (1992)); however, the R--S--NO.fwdarw.NO reaction is kinetically complicated and difficult to control (Morley et al., J. Cardiovasc. Pharmacol., 21, 670-676 (1993)). Similarly, compounds like molsidomine and linsidomine not only require activation to release NO, but they also release undesirable free radicals. The NONOates, therefore, are thus unique among currently known drugs in that they decompose at any given pH by a first-order reaction to provide doses of nitric oxide that can be predicted, quantified, and controlled. See, e.g., Maragos et al., supra.
Nitric oxide/nucleophile complexes which release nitric oxide in aqueous solution are also disclosed in U.S. Pat. Nos. 5,039,705, 5,155,137, 5,185,376, 5,208,233, 5,212,204, 5,250,550, 5,366,977 and 5,389,675, as being useful cardiovascular agents (see also Maragos et al., J. Med. Chem., 34, 3242-3247 (1991)).
Despite the promise of the nitric oxide/nucleophile adducts that have been investigated, their pharmacological application has been limited by their tendency to distribute evenly throughout the medium. Such even distribution is a great advantage in many research applications, but tends to compromise their selectivity of action. Another limitation to the application of these nitric oxide/nucleophile adducts is their propensity for relatively rapid release of nitric oxide, which may necessitate frequent dosing to achieve a prolonged biological effect. The nitric oxide-releasing polymers of the present invention overcome these limitations by enabling concentrated and localized release of NO at a given site in a controllable and predictable manner such that effective dosing may be realized.
There remains a need, however, for an effective method of preventing, ameliorating and treating restenosis. Accordingly, the present invention provides a method of prevention, amelioration and treatment for restenosis and related disorders which overcomes the disadvantages of currently available treatment methods, and delivery means for use in the prevention, amelioration and treatment of restenosis and related disorders. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.